Rapid photochemical inactivation of Ca²⁺-antagonists shows that Ca²⁺ entry directly activates contraction in frog heart

Abstract

‘Calcium-antagonists’ are a group of pharmacological agents which are potent vasodilators and are clinically used for the treatment of angina. They are thought to block Ca²⁺ channels in vascular smooth muscle^1,2 and myocardium^3–5 but other sites of action have been proposed⁶. These agents bind tightly to heart muscle and suppress action potential and contraction. Nifedipine and nisoldipine (BAY K 5552) are Ca²⁺ antagonists which have o-nitrobenzyl groups and are photolabile⁷. We have found that short pulses of UV light rapidly inactivate these drugs in ventricular muscle. This observation allowed us to study the effect of Ca²⁺ antagonists on action potential, Ca²⁺ current and tension in conditions in which diffusion of those drugs from their site of action was not rate limiting. Our studies, described here, suggest that the primary mechanism of action of Ca²⁺ antagonists is the blockade of the Ca²⁺ channel and support the idea that extracellular space is the immediate source of contractile Ca²⁺ in the frog heart.